B-cell-specific signatures reveal novel immunophenotyping and therapeutic targets for hepatocellular carcinoma.

BACKGROUND: Immunotherapy presents both promises and challenges in treating hepatocellular carcinoma (HCC) due to its complex immunological microenvironment. The role of B cells, a key part of the immune system, remains uncertain in HCC. AIM: To identify B-cell-specific signatures and reveal novel immunophenotyping and therapeutic targets for HCC. METHODS: Using the Tumor Immune Single-cell Hub 2 database, we identified B-cell-related genes (BRGs) in HCC. Gene enrichment analysis was performed to explore the possible collaboration between B cells and T cells in HCC. We conducted univariate Cox regression analysis using The Cancer Genome Atlas liver HCC collection dataset to find BRGs linked to HCC prognosis. Subsequently, least absolute shrinkage and selection operator regression was utilized to develop a prognostic model with 11 BRGs. The model was validated using the International Cancer Genome Consortium dataset and GSE76427. RESULTS: The risk score derived from the prognostic model emerged as an independent prognostic factor for HCC. Analysis of the immune microenvironment and cell infiltration revealed the immune status of various risk groups, supporting the cooperation of B and T cells in suppressing HCC. The BRGs model identified new molecular subtypes of HCC, each with distinct immune characteristics. Drug sensitivity analysis identified targeted drugs effective for each HCC subtype, enabling precision therapy and guiding clinical decisions. CONCLUSION: We clarified the role of B cells in HCC and propose that the BRGs model offers promising targets for personalized immunotherapy.

Gender, BMI, and Age-Related Variations in Lower Limb Alignment Parameters and CPAK Phenotypes in Chinese Patients with Knee Osteoarthritis.

OBJECTIVES: Research on the distribution of and the variation in coronal plane alignment of the knee (CPAK) in the Chinese osteoarthritis population is limited. We aimed to establish the CPAK classification based on the characteristics of lower limb alignment in the Chinese osteoarthritis population. We also investigated variations in lower limb alignment parameters and CPAK phenotypes based on gender, body mass index (BMI), and age. METHODS: A retrospective study was conducted on a total of 944 knees diagnosed with osteoarthritis in 479 patients from January 2017 to December 2023. A scatterplot was used to describe the distribution of the CPAK classification, and the differences in lower limb alignment parameters and the CPAK classification were compared across genders (male, female), ages (middle-aged/<65 years, elderly/≥65 years), and BMI categories (normal/<25 kg/m2, overweight and obese/≥25 kg/m2) using the chi-squared test or Fisher's exact test. RESULTS: The average arithmetic hip-knee-ankle angle and joint line obliquity (JLO) were -3.03° ± 5.69° and 174.45° ± 4.29°, respectively. There was a higher prevalence of constitutional varus alignment in males and the overweight or obese group, while constitutional valgus alignment was more common in females and the normal BMI group (p < 0.05). Additionally, females had a greater apex distal JLO than males (p < 0.05). There were no statistically significant differences in lower limb alignment parameters among different age groups (p > 0.05). Although there were variations in alignment parameters across different genders and BMI categories in the knee osteoarthritis population, the predominant CPAK classifications were type I (38.03%), followed by type II (20.02%) and type IV (17.06%). CONCLUSION: The most common CPAK types were I, II, and IV, and they were not influenced by gender, BMI, or age, indicating that the CPAK classification can reliably reflect constitutional alignment. A better understanding of native alignment variability can aid in providing patient-specific recommendations when considering orthopedic alignment strategies.

Anatomical and dosimetric variations during volumetric modulated arc therapy in patients with locally advanced nasopharyngeal carcinoma after induction therapy: Implications for adaptive radiation therapy.

Purpose: To investigate anatomical and dosimetric changes during volumetric modulated arc therapy (VMAT) in patients with locally advanced nasopharyngeal carcinoma (LA-NPC) after induction therapy (IT) and explore characteristics of patients with notable variations. Materials and methods: From July 2021 to June 2023, 60 LA-NPC patients undergoing VMAT after IT were retrospectively recruited. Adaptive computed tomography (aCT), reconstructed from weekly cone-beam computed tomography(CBCT), facilitates recontouring and planning transplantation. Volume, dice similarity coefficients, and dose to target volumes and organs at risk(OARs) on planning CT(pCT) and aCT were compared to identify changing patterns. Multivariate logistic regression was used to investigate risk factors. Results: The volumes of PGTVnasopharynx (PGTVp), PGTVnode (PGTVn), ipsilateral and contralateral parotid glands decreased during VMAT, with reductions of 2.25 %, 6.98 %, 20.09 % and 18.00 %, respectively, at 30 fractions from baseline (P < 0.001). After 25 fractions, D99 and D95 of PGTVn decreased by 7.94 % and 4.18 % from baseline, respectively, while the Dmean of ipsilateral and contralateral parotid glands increased by 7.80 % and 6.50 %, marking the peak rates of dosimetric variations (P < 0.001). The dosimetric fluctuations in PGTVp, the brainstem, and the spinal cord remained within acceptable limits. Furthermore, an initial BMI ≥ 23.5 kg/m2 and not-achieving objective response (OR) after IT were regarded as risk factors for a remarkable PGTVn dose reduction in the later stages of VMAT. Conclusions: Replanning for post-IT LA-NPC patients appears reasonable at 25F during VMAT. Patients with an initial BMI ≥ 23.5 kg/m2 and not-achieving OR after IT should be considered for adaptive radiation therapy to stabilize the delivered dose.

ASH1L in Hepatoma Cells and Hepatic Stellate Cells Promotes Fibrosis-Associated Hepatocellular Carcinoma by Modulating Tumor-Associated Macrophages.

Hepatocellular carcinoma (HCC) often occurs in the context of fibrosis or cirrhosis. Methylation of histone is an important epigenetic mechanism, but it is unclear whether histone methyltransferases are potent targets for fibrosis-associated HCC therapy. ASH1L, an H3K4 methyltransferase, is found at higher levels in activated hepatic stellate cells (HSCs) and hepatoma cells. To determine the role of ASH1L in vivo, transgenic mice with conditional Ash1l depletion in the hepatocyte cell lineage (Ash1lflox/floxAlbcre) or HSCs (Ash1lflox/floxGFAPcreERT2) are generated, and these mice are challenged in a diethylnitrosamine (DEN)/carbon tetrachloride (CCl4)-induced model of liver fibrosis and HCC. Depleting Ash1l in both hepatocytes and HSCs mitigates hepatic fibrosis and HCC development. Multicolor flow cytometry, bulk, and single-cell transcriptomic sequencing reveal that ASH1L creates an immunosuppressive microenvironment. Mechanically, ASH1L-mediated H3K4me3 modification increases the expression of CCL2 and CSF1, which recruites and polarizes M2-like pro-tumorigenic macrophages. The M2-like macrophages further enhance tumor cell proliferation and suppress CD8+ T cell activation. AS-99, a small molecule inhibitor of ASH1L, demonstrates similar anti-fibrosis and tumor-suppressive effects. Of pathophysiological significance, the increased expression levels of mesenchymal ASH1L and M2 marker CD68 are associated with poor prognosis of HCC. The findings reveal ASH1L as a potential small-molecule therapeutic target against fibrosis-related HCC.

Roles of noncoding RNA in allergic rhinitis.

BACKGROUND: Allergic rhinitis (AR) is one of the most common respiratory noninfectious diseases and chronic inflammatory diseases, the incidence of which has been increasing in recent years. The main pathological characteristics of AR are repeated inflammation, airway hyperreactivity, mucus hypersecretion, and reversible airway obstruction due to inflammatory cell response. AR occurrence is associated with various factors, including those of genetic and environmental origins. Noncoding RNAs (ncRNAs) are a group of RNA molecules that cannot be converted into polypeptides. The three main categories of ncRNAs include microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs). NcRNAs play a crucial role in controlling gene expression and contribute to the development of numerous human diseases. METHODS: Articles are selected based on Pubmed's literature review and the author's personal knowledge. The largest and highest quality studies were included. The search selection is not standardized. Several recent studies have indicated the relationship of ncRNAs with the development of respiratory allergic diseases. NcRNAs, including miRNAs, lncRNAs, and circRNAs, are important gene expression regulatory factors. We review the expression and function of ncRNAs in AR, their role as disease biomarkers, and their prospective applicability in future research and clinically. We also discuss interactions between ncRNAs and their influence on AR comprehensively, these interactions are essential for determining the underlying pathological mechanisms further and discovering new drug therapeutic targets. RESULTS: NcRNAs can be used as biomarkers for early AR diagnosis, disease surveillance and prognosis assessment. Various categories of ncRNAs play distinct yet interconnected roles and actively contribute to intricate gene regulatory networks. They are also therapeutic targets and biomarkers in other allergic diseases. CONCLUSION: This article demonstrates ncRNAs have a wide range of applications in AR treatment. The database covers three key areas: miRNAs, lncRNAs, and circRNAs. Additionally, potential avenues for future research to facilitate the practical application of ncRNAs as therapeutic targets and biomarkers will be explore. With further research and technological development, ncRNAs may provide additional innovative, effective solutions for AR treatment.

Magnetic navigation-assisted colonoscopic enteral tube placement in swine (with video): a preliminary study.

BACKGROUND: Colonoscopic enteral tube placement using current methods has some shortcomings, such as the complexity of the procedure and tube dislodgement. The magnetic navigation technique (MNT) has been proven effective for nasoenteral feeding tube placement, and is associated with reduced cost and time to initiation of nutrition. This study attempted to develop a novel method for enteral tube placement using MNT. METHODS: The MNT device consisted of an external magnet and a 12 Fr tube with a magnet at the end. Ten swine were used, and bowel cleansing was routinely performed before colonoscopy. Intravenous anesthesia with propofol and ketamine was administered. A colonoscopic enteral tube was placed using the MNT. The position of the end of the enteral tube was determined by radiography, and angiography was performed to check for colonic perforations. Colonoscopy was used to detect intestinal mucosal damage after tube removal. RESULTS: MNT-assisted colonoscopic enteral tube placement was successfully completed in all pigs. The median operating time was 30 (26-47) min. No colon perforation was detected on colonography after enteral tube placement, and no colonic mucosal bleeding or injury was detected after the removal of the enteral tube. CONCLUSIONS: MNT-assisted colonoscopic enteral tube placement is feasible and safe in swine and may represent a valuable method for microbial therapy, colonic drainage, and host-microbiota interaction research in the future.

Novel mutation in XPNPEP3 in a patient with heart failure without nephronophthisis-like nephropathy (NPHPL1): case report and literature review.

BACKGROUND X-PROLYL AMINOPEPTIDASE 3: (XPNPEP3) mutations are known to cause nephronophthisis-like nephropathy-1 (NPHPL1), a rare autosomal-recessive kidney disease characterized by progressive kidney failure and cystic kidney disease in childhood. The full phenotypic spectrum associated with mutations in XPNPEP3 is not fully elucidated. CASE PRESENTATION: A 13-year-old Chinese female patient with intellectual disability presented with a 2-year history of convulsions and fatigue, with a recent episode of swelling, breathlessness, and nocturnal dyspnea lasting 10 days. The patient was diagnosed with heart failure and kidney failure. Whole exome sequencing revealed a homozygous c.970-2 A > G mutation in XPNPEP3 associated with severe cardiac dysfunction and neurological symptoms, including epilepsy and intellectual disability. Notably, kidney ultrasound did not reveal the typical changes of NPHPL1, and kidney failure was hypothesized to be secondary to cardiac dysfunction rather than primary kidney pathology. CONCLUSIONS: This case suggests the possible association of additional phenotypic features associated with XPNPEP3 mutations, emphasizing the need for further investigation into the heterogeneous clinical presentations associated with XPNPEP3 mutations. The findings highlight the importance of considering alternative phenotypes in patients with genetic mutations traditionally associated with specific diseases. Segregation and functional analyses are necessary to determine causality between the c.970-2 A > G XPNPEP3 mutation and disease.

ChatGPT-4 and wearable device assisted Intelligent Exercise Therapy for co-existing Sarcopenia and Osteoarthritis (GAISO): a feasibility study and design for a randomized controlled PROBE non-inferiority trial.

BACKGROUND: Sarcopenia and osteoarthritis are prevalent age-related diseases that mutually exacerbate each other, creating a vicious cycle that worsens both conditions. Exercise is key to breaking this detrimental cycle. Facing increasing demand for rehabilitation services within this patient demographic, ChatGPT-4 and wearable device may increase the availability, efficiency and personalization of such health care. AIM: To evaluate the clinical efficacy and cost-effectiveness of a rehabilitation system implemented on mobile platforms, utilizing the integration of ChatGPT-4 and wearable devices. METHODS: The study design is a prospective randomized open blinded end-point (PROBE) non-inferiority trial. 278 patients diagnosed with osteoarthritis and sarcopenia will be recruited and randomly assigned to the intervention group and the control group. In the intervention group patients receive mobile phone-based rehabilitation service where ChatGPT-4 generates personalized exercise therapy, and wearable device guides and monitor the patient to implement the exercise therapy. Traditional clinic based face-to-face exercise therapy will be prescribed and implemented in the control group. All patients will receive three-months exercise therapies following the frequency, intensity, type, time, volume and progression (FITT-VP) principle. The patients will be assessed at baseline, one month, three months, and six months after initiation. Outcome measures will include ROM, gait patterns, Visual Analogue Scale (VAS) for pain assessment, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Knee Injury and Osteoarthritis Outcome Score (KOOS) for functional assessment, Short-Form Health Survey 12 (SF-12) for quality of life, Minimal Clinically Important Difference (MCID), Patient Acceptable Symptom State (PASS), and Substantial Clinical Benefit (SCB) for clinically significant measures. DISCUSSION: A rehabilitation system combining the capabilities of ChatGPT-4 and wearable devices potentially enhance the availability and efficiency of professional rehabilitation services, thus enhancing the therapeutic outcomes for a substantial population concurrently afflicted with sarcopenia and osteoarthritis.

Identification of key genes participating in copper-diethyldithiocarbamate-related cell death process and predicting the development of prostate cancer.

Copper (Cu) is used as a cofactor in all organisms, and yet it can be toxic at high intracellular concentrations, causing cell death. Diethyldithiocarbamate (DDC) is a Cu ionophore that can transport Cu effectively into the cell. Copper-diethyldithiocarbamate (Cu-DDC) can treat prostate cancer (PCa) and may correlate with the cell death process. However, the specific Cu-DDC-related cell death genes in PCa are still unknown. Information about the Cu-DDC-related cell death genes was obtained from a previous study. Concurrently, the RNA expression profiles and clinical data were downloaded from public databases such as GEO, TCGA, and CPGEA. Using data from TCGA database, the logistic and lasso regression models were generated using R software. The influence of these genes in affecting PCa progression and prognosis was analyzed. Finally, the expression of these genes was verified in clinical samples. We found five Cu-DDC-related cell death genes associated with the occurrence of PCa from GSE35988, a gene dataset, namely, CDKN2A, PRC1, CDK1, SOX2, and ZNF365. CDKN2A, PRC1, and CDK1 are known to influence PCa patients' disease-free survival (DFS) status and were overexpressed, whereas SOX2 and ZNF365 were under-expressed in PCa in the different databases. Some of these genes can affect PCa progression. Consistent with the database results, the mRNA and protein expression of CDKN2A, PRC1, and CDK1 was also higher in clinical samples. In conclusion, we identified five hub genes which are important for Cu-DDC-related cell death process that can predict the development of PCa.

A Nomogram Based on a Non-Invasive Method to Distinguish Between Gram-Positive and Gram-Negative Bacterial Infections of Liver Abscess.

Purpose: The diagnosis of liver abscess (LA) caused by Gram-positive bacteria (GPB) and Gram-negative bacteria (GNB) depends on ultrasonography, but it is difficult to distinguish the overlapping features. Valuable ultrasonic (US) features were extracted to distinguish GPB-LA and GNB-LA and establish the relevant prediction model. Materials and Methods: We retrospectively analyzed seven clinical features, three laboratory indicators and 11 US features of consecutive patients with LA from April 2013 to December 2023. Patients with LA were randomly divided into training group (n=262) and validation group (n=174) according to a ratio of 6:4. Univariate logistic regression and LASSO regression were used to establish prediction models. The performance of the model was evaluated using area under the curve(AUC), calibration curves, and decision curve analysis (DCA), and subsequently validated in the validation group. Results: A total of 436 participants (median age: 55 years; range: 42-68 years; 144 women) were evaluated, including 369 participants with GNB-LA and 67 with GPB-LA, respectively. A total of 11 predictors by LASSO regression analysis, which included gender, age, the liver background, internal gas bubble, echogenic debris, wall thickening, whether the inner wall is worm-eaten, temperature, diabetes mellitus, hepatobiliary surgery and neutrophil(NEUT). The performance of the Nomogram prediction model distinguished between GNB-LA and GPB-LA was 0.80, 95% confidence interval [CI] (0.73-0.87). In the validation group, the AUC of GNB was 0.79, 95% CI (0.69-0.89). Conclusion: A model for predicting the risk of GPB-LA was established to help diagnose pathogenic organism of LA earlier, which could help select sensitive antibiotics before the results of drug-sensitive culture available, thereby shorten the treatment time of patients.

GB18-06, a nanobody targeting GDF15, effectively alleviates weight loss and restores physical function in cachexia models.

Cachexia is a complicated metabolic syndrome mainly associated with cancers, characterized by extreme weight loss and muscle wasting. It is a debilitating condition that negatively affects prognosis and survival. However, there is currently no effective pharmacological intervention that can reverse body weight loss and improve physical performance in patients with cachexia. Growth differentiation factor 15 (GDF15) can suppress appetite and regulate energy balance through binding to glial cell-derived neurotrophic factor receptor alpha-like (GFRAL). In order to develop a novel, effective treatment for cachexia, we generated a GDF15-targeting VHH nanobody, GB18-06, that was able to bind GDF15 with high affinity. In vitro, GB18-06 potently inhibited the GDF15-GFRAL signaling pathway, leading to a reduction of downstream ERK and AKT phosphorylation levels; in vivo, GB18-06 alleviated weight loss (>20%) in cancer and chemotherapy-induced cachexia models in mice. Compared with the control (phosphate-buffered saline) group, the ambulatory activity of mice in the GB18-06-treated group also increased 77%. Furthermore, GB18-06 exhibited desirable pharmacokinetic properties and an excellent developability profile. Our study has demonstrated a means of developing targeted treatment for cachexia with high efficacy, potentially leading to improved clinical outcomes and quality of life for patients with cachexia.

ADT-1004: A First-in-Class, Orally Bioavailable Selective pan-RAS Inhibitor for Pancreatic Ductal Adenocarcinoma.

Here, we evaluated in vivo antitumor activity, target engagement, selectivity, and tumor specificity of ADT-1004, an orally bioavailable prodrug of ADT-007 having highly potent and selective pan-RAS inhibitory activity. ADT-1004 strongly blocked tumor growth and RAS activation in mouse PDAC models without discernable toxicity. As evidence of target engagement and tumor specificity, ADT-1004 inhibited activated RAS and ERK phosphorylation in PDAC tumors at dosages approximately 10-fold below the maximum tolerated dose and without discernable toxicity. ADT-1004 inhibited ERK phosphorylation in PDAC tumors. In addition, ADT-1004 blocked tumor growth and ERK phosphorylation in PDX PDAC models with KRAS G12D , KRAS G12V , KRAS G12C , or KRAS G13Q mutations. ADT-1004 treatment increased CD4 + and CD8 + T cells in the TME consistent with exhaustion and increased MHCII + M1 macrophage and dendritic cells. ADT-1004 demonstrated superior efficacy over sotorasib and adagrasib in tumor models involving human PDAC cells resistant to these KRAS G12C inhibitors. As evidence of selectivity for tumors from PDAC cells with mutant KRAS, ADT-1004 did not impact the growth of tumors from RAS WT PDAC cells. Displaying broad antitumor activity in multiple mouse models of PDAC, along with target engagement and selectivity at dosages that were well tolerated, ADT-1004 warrants further development. Significance: ADT-1004 displayed robust antitumor activity in aggressive and clinically relevant PDAC models with unique tumor specificity to block RAS activation and MAPK signaling in RAS mutant cells. As a pan-RAS inhibitor, ADT-1004 has broad activity and potential efficacy advantages over allele-specific KRAS inhibitors by averting resistance. These findings support clinical trials of ADT-1004 for KRAS mutant PDAC.

Associations between peripheral whole blood cell counts derived indexes and cancer prognosis: An umbrella review of meta-analyses of cohort studies.

Meta-analyses have reported conflicting data on the whole blood cell count (WBCC) derived indexes (neutrophil-to-lymphocyte ratio [NLR], platelet-to-lymphocyte ratio [PLR], and lymphocyte-to-monocyte ratio [LMR]) and cancer prognosis. However, the strength and quality of this evidence has not been quantified in aggregate. To grade the evidence from published meta-analyses of cohort studies that investigated the associations between NLR, PLR, and LMR and cancer prognosis. A total of 694 associations from 224 articles were included. And 219 (97.8%) articles rated as moderate-to-high quality according to AMSTAR. There were four associations supported by convincing evidence. Meanwhile, 165 and 164 associations were supported by highly suggestive and suggestive evidence, respectively. In this umbrella review, we summarized the existing evidence on the WBCC-derived indexes and cancer prognosis. Due to the direction of effect sizes is not completely consistent between studies, further research is needed to assess causality and provide firm evidence.

Guiding induction chemotherapy of locoregionally advanced nasopharyngeal carcinoma with ternary classification of predicted individual treatment effect.

BACKGROUND AND PURPOSE: Induction chemotherapy (IC) before concurrent chemoradiotherapy does not universally improve long-term overall survival (OS) in locoregionally advanced nasopharyngeal carcinoma (LANPC). Conventional risk stratification often yields suboptimal IC decisions. Our study introduces a ternary classification of predicted individual treatment effect (PITE) to guide personalized IC decisions. MATERIALS AND METHODS: A two-center retrospective analysis of 1,213 patients with LANPC was conducted to develop and validate prognostic models integrating magnetic resonance imaging and clinical data to estimate individual 5-year OS probabilities for IC and non-IC treatments. Differences in these probabilities defined PITE, facilitating patient stratification into three IC recommendation categories. Model effectiveness was validated using Kaplan-Meier estimators, decision curve-like analysis, and evaluations of variable importance and distribution. RESULTS: The models exhibited strong predictive performance in both treatments across training and cross-validation sets, enabling accurate PITE calculations and patient classification. Compared with non-IC treatment, IC markedly improved OS in the IC-preferred group (HR = 0.62, p = 0.02), had no effect in the IC-neutral group (HR = 1.00, p = 0.70), and worsened OS in the IC-opposed group (HR = 2.00, p = 0.03). The ternary PITE classification effectively identified 41.7 % of high-risk patients not benefiting from IC, and yielded a 2.68 % higher mean 5-year OS probability over risk-based decisions. Significantly increasing distributions of key prognostic indicators, such as metastatic lymph node number and plasma Epstein-Barr virus DNA level from IC-opposed to IC-preferred groups, further validated the clinical relevance of PITE classification. CONCLUSION: The ternary PITE classification offers an accurate and clinically advantageous approach to guide personalized IC decision-making in patients with LANPC.

Effect of Simulated Cosmic Radiation on Cytomegalovirus Reactivation and Lytic Replication.

Human exploration of the solar system will expose crew members to galactic cosmic radiation (GCR), with a potential for adverse health effects. GCR particles (protons and ions) move at nearly the speed of light and easily penetrate space station walls, as well as the human body. Previously, we have shown reactivation of latent herpesviruses, including herpes simplex virus, Varicella zoster virus, Epstein-Barr virus, and cytomegalovirus (CMV), during stays at the International Space Station. Given the prevalence of latent CMV and the known propensity of space radiation to cause alterations in many cellular processes, we undertook this study to understand the role of GCR in reactivating latent CMV. Latently infected Kasumi cells with CMV were irradiated with 137Cs gamma rays, 150 MeV protons, 600 MeV/n carbon ions, 600 MeV/n iron ions, proton ions, and simulated GCR. The CMV copy number increased significantly in the cells exposed to radiation as compared with the non-irradiated controls. Viral genome sequencing did not reveal significant nucleotide differences among the compared groups. However, transcriptome analysis showed the upregulation of transcription of the UL49 ORF, implicating it in the switch from latent to lytic replication. These findings support our hypothesis that GCR may be a strong contributor to the reactivation of CMV infection seen in ISS crew members.

Association between microsatellite instability status, clinicopathological features and mitochondrial DNA amplification in patients with colorectal cancer.

The relationship between BRAF-V600E mutations, mitochondrial DNA amplification and microsatellite instability-high (MSI-H) in colorectal cancer (CRC) has yet to be fully elucidated. The aim of the present study was to assess the association between the MSI status and BRAF-V600E gene mutations/clinicopathological features/mitochondrial DNA amplification in CRC. A non-interventional study analysis was performed using the clinicopathological features of 455 patients with CRC. Immunohistochemistry was used to evaluate four mismatch repair proteins (MutS homolog 2, MutS homolog 6, MutL homolog 1 and postmeiotic segregation increased 2), Ki-67 index, and programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) expression. Additionally, PCR coupled with capillary electrophoresis were used to ascertain the MSI status. Moreover, amplification refractory mutation system-PCR was used to detect BRAF-V600E gene mutation and fluorescence in situ hybridization analysis was used to assess mitochondrial DNA. A total of 455 patients were divided into the MSI high (MSI-H) group (n=52) and microsatellite stability (MSS) group (n=403) based on their MSI status. Compared with the results of immunohistochemistry of four mismatch repair proteins, the consistency rate between mismatch repair protein deficiency and MSI was 94.23%. There were significant differences in PD-L1, primary tumor site, clinical stage, degree of differentiation, tumor size, lymph node metastasis and the occurrence of multiple primary tumors between the MSI-H group and MSS group (P<0.05 or P<0.001). However, there were no significant differences for sex, age, PD-1, Ki-67 expression and BRAF-V600E. The 24-60-month survival rate of the patients in the MSI-H group was significantly higher than that of those in the MSS group (P<0.05). Furthermore, the number of mitochondrial DNA was significantly amplified in the MSI-H group. In conclusion, the present study demonstrated that the combined detection of PD-L1 and MSI in patients with CRC can provide more accurate and effective guidance for personalized treatment.

ITGA5 is associated with prognosis marker and immunosuppression in head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is a major tumor that seriously threatens the health of the head and neck or mucosal system. It is manifested as a malignant phenotype of high metastasis and invasion caused by squamous cell transformation in the tissue area. Therefore, it is necessary to search for a biomarker that can systematically correlate and reflect the prognosis of HNSCC based on the characteristics of head and neck tumors. METHODS: Based on TCGA-HNSCC data, R software was used to analyze gene expression, correlation, Venn diagram, immune invasive and immunosuppressive phenotypes respectively. The intrinsic effect of ITGA5 on the malignant phenotype of HNSCC cells was verified by cell experiments. Immunohistochemical images from The Human Protein Atlas (THPA) database display the differences in the expression of related proteins in HNSCC tissues. Based on functional enrichment and correlation analysis, the prognostic value of ITGA5 for HNSCC was explored, and the expression level of ITGA5 may affect the chemotherapy of targeting the PI3K-AKT. RESULTS: In this study, the target gene ITGA5 may be identified as a valuable prognostic marker for HNSCC. The results of enrichment analysis showed that ITGA5 was mainly involved in the dynamic process of extracellular matrix, which may affect the migration or metastasis of tumor cells. Meanwhile, ITGA5 may be closely related to the infiltration of M2 macrophages, and its secretory phenotypes TGFB1, PDGFA and PDGFB may affect the immunosuppressive phenotypes of tumor cells, which reflects the systemic influence of ITGA5 in HNSCC. In addition, the expression levels of ITGA5 were negatively correlated with the efficacy of targeting PI3K-AKT chemotherapy. CONCLUSION: ITGA5 can be used as a potential marker to systematically associate with prognosis of HNSCC, which may be associated with HNSCC malignant phenotype, immunosuppression and chemotherapy resistance.

Identifying Predictors of Smoking Switching Behaviours Among Adult Smokers in the United States: A Machine Learning Approach.

Completely abstaining from cigarette smoking or fully switching to e-cigarette (EC) use may be beneficial for reducing the global burden of smoking-related diseases. This study aimed to identify and compare the top 10 prospective predictors of smokers switching away from smoking in the United States. Data from adult exclusive cigarette smokers at Wave 4 of the Population Assessment of Tobacco and Health (PATH) study, who were followed up at Wave 6, were analysed. An Xgboost-based machine learning (ML) approach with a nested cross-validation scheme was utilised to develop a multiclass predictive model to classify smokers' behavioural changes from W4 to W6, including smoking cessation, full and partial switching to EC, and cigarette non-switching. The SHapley Additive exPlanations (SHAP) algorithm was deployed to interpret the top 10 predictors of each switching behaviour. A total of 396 variables were selected to generate the four-class prediction model, which demonstrated a micro- and macro-average area under the receiver operating characteristics curve (ROC-AUC) of 0.91 and 0.81, respectively. The top three predictors of smoking cessation were prior regular EC use, age, and household rules about non-combusted tobacco. For full switching to EC use, the leading predictors were age, type of living space, and frequency of social media visits. For partial switching to EC use, the key predictors were daily cigarette consumption, the time from waking up to smoking the first cigarette, and living with tobacco users. ML is a promising technique for providing comprehensive insights into predicting smokers' behavioural changes. Public health interventions aimed at helping adults switch away from smoking should consider the predictors identified in this study.

Five-year radiological outcomes between decompression alone and decompression with an interlaminar device for lumbar spinal stenosis.

Background: There is limited literature regarding radiological outcomes in the use of interlaminar devices as an adjunct to decompression compared to decompression alone (DA) for symptomatic lumbar spinal stenosis (LSS). This study aims to assess and compare 5-year radiological outcomes following spinal decompression and decompression with ILD (D + ILD). Methods: We conducted a retrospective review of prospectively collected data of 94 patients who underwent spinal decompression with or without ILD insertion between 2007-2015. Patients with symptomatic LSS who met the study criteria were offered spinal decompression with or without ILD insertion. Those patients who accepted ILD insertion were placed in the D + ILD group (n=39); while those opting for DA, were placed in the DA group (n=55). Radiological indices were assessed preoperatively, immediate post-operative, 2 years and 5 years postoperatively. Results: There were a total of 94 patients with 55 in the DA group and 39 in the D + ILD group. In both groups, there was no significant change post-operatively in the sagittal balance parameters namely, the mean pelvic incidence, pelvic tilt, sacral slope and pelvic incidence minus lumbar lordosis (PI - LL) during the 5-year follow-up. Comparing between the groups, there was no significant difference in sagittal balance parameters. Comparing between DA versus D + ILD, there was no significant difference in overall lordosis, but the D + ILD had a significant reduction in sagittal angle (at the index level) of 2.3° compared to the DA group (P=0.01). In the control group, there was no significant difference in the anterior disc, posterior disc and foraminal height post-operatively. In the D + ILD group, there was a significant mean increase of 1.3 mm in anterior disc height, 1.8 mm in posterior disc height and 4.7 mm in foraminal height compared to the control group. In both groups, there was significant improvement in all clinical outcomes namely 36-item short form survey physical component summary (SF36 PCS), 36-item short form survey mental component summary (SF36 MCS) and visual analogue scale (VAS). Comparing the groups, there was significant improvement in the D + ILD group in SF36 MCS (P=0.01) but no difference in SF36 PCS or VAS. Reoperation rates were equivalent. Conclusions: Our study found that in the management of lumbar stenosis, the use of an ILD as an adjunct device compared to DA had significant improvement in anterior disc, posterior disc and foraminal height with expected focal kyphosis at the level of intervention without change in the lumbar lordosis and sagittal balance at 5 years.

Higher triglyceride glucose-waist height ratio index is associated with higher prevalence of gallstone: a population-based study.

Background: The aim of this study is to evaluate the association between triglyceride glucose-waist height ratio (TyG-WHtR) index and the prevalence of gallstone disease (GSD), alongside the age at first gallstone surgery among adult populations within the United States. Methods: We screened participants using the National Health and Nutrition Examination Survey (NHANES). Logistic regression analysis, generalized additive modeling, smoothed curve fitting, and subgroup analysis were employed to assess the association between the TyG-WHtR index, prevalence of GSD, and the age at initial gallstone surgical intervention. Results: In this study, 3,728 participants were enrolled, among whom 395 individuals reported a prior history of GSD. The association between the TyG-WHtR index and the prevalence of GSD demonstrated a non-linear, positive association. After adjusting for all potential confounders, for each incremental unit rise in the TyG-WHtR index, there was a 47% escalation in the prevalence of GSD (OR = 1.47, 95% CI: 1.29, 1.68). Subgroup analyses indicated a more pronounced association between the TyG-WHtR index and the prevalence of GSD among individuals aged 20-80 years, females, non-Hispanic white population, non-Hispanic black population, other racial groups, and non-diabetic cohorts. Additionally, this study identified that the TyG-WHtR index may be negatively correlated with age at first surgical treatment of gallstones. Conclusion: An elevated TyG-WHtR index demonstrates a positive association with the prevalence of GSD. However, more prospective studies are needed to validate our findings.